Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase
Imidazopyridine and Pyrazolopiperidine Derivatives as Novel Inhibitors of Serine Palmitoyl Transferase
复制标题
DOI：
10.1021/acs.jmedchem.5b01851
复制
发表时间：
2016-06-23
影响因子：
7.3
通讯作者：
Brozinick, Joseph T.
中科院分区：
文献类型：
--
作者：
Genin, Michael J.;Valcarcel, Isabel C. Gonzalez;Brozinick, Joseph T.
为了开发2型糖尿病和血脂异常的新疗法，我们寻求丝氨酸棕榈酰转移酶（SPT）的抑制剂。为此，化合物1和2在体外被开发为有效的SPT抑制剂。1和2降低啮齿动物中的血浆神经酰胺，在DIO小鼠中具有增强胰岛素敏化的轻微趋势，并且在胆固醇/胆酸喂养的大鼠中降低甘油三酯并升高HDL。不幸的是，这些分子在大鼠慢性给药后引起胃肠病。
To develop novel treatments for type 2 diabetes and dyslipidemia, we pursued inhibitors of serine palmitoyl transferase (SPT). To this end compounds 1 and 2 were developed as potent SPT inhibitors in vitro. 1 and 2 reduce plasma ceramides in rodents, have a slight trend toward enhanced insulin sensitization in DIO mice, and reduce triglycerides and raise HDL in cholesterol/cholic acid fed rats. Unfortunately these molecules cause a gastric enteropathy after chronic dosing in rats.